Preparation and administration form comprising an acid-labile active compound

ABSTRACT

Novel administration forms and preparation for acid-labile active compounds are described. The novel administration forms contain individual active compound units, the active compound being present in the active compound units in a matrix made of a mixture comprising at least one fatty alcohol and at least one solid paraffin, in a matrix made of a mixture of a triglyceride and at least one solid paraffin or in a matrix made of a mixture comprising at least one fatty acid ester and at least one solid paraffin. In particular, the active compound units are microspheres which can be produced by prilling.

This application is a continuation application of U.S. Ser. No.09/980,492, filed Dec. 4. 2001, which was filed under 35 U.S.C. 371 as anational stage of PCT/EP00/04958, filed May 31, 2000.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical technologyand describes a novel administration form comprising an acid-labileactive compound, in particular an acid-labile proton pump inhibitor.Furthermore, the invention also relates to processes for the productionof the administration form, preparations which can be used for theproduction of the administration form, and a process for the productionof the preparations.

PRIOR ART

It is generally known to coat peroral administration forms, e.g. tabletsor pellets which contain an acid-labile active compound, with an entericcoating which, after passage through the stomach, rapidly dissolves inthe alkaline medium of the intestine. Examples of such acid-labileactive compounds are acid-labile proton pump inhibitors (H⁺/K⁺ ATPaseinhibitors), in particular pyridin-2-ylmethylsulfinyl-1H-benzimidazoles,such as are disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287,EP-A-0 174 726 and EP-A-0 268 956. On account of their H⁺/K⁺ATPase-inhibiting action, these are of importance in the therapy ofdiseases which are due to increased gastric acid secretion. Examples ofactive compounds from this group which are already commerciallyavailable are5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole) and2-{([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulfinyl}-1H-benzimidazole(INN: rabeprazole).

Because of their strong tendency to decompose in a neutral and, inparticular, in an acidic environment, where strongly coloreddecomposition products are also formed, for oral preparations it is alsonecessary in this case to protect the active compounds from the actionof acids. In the case of the strongly acid-labilepyridin-2-ylmethylsulfinyl-1H-benzimidazoles, it is moreover necessaryto process these in the tablet core or in pellets in the form of theiralkaline salts, for example as sodium salts, or together with alkalinesubstances. Since the substances suitable for enteric coatings are thosehaving free carboxyl groups, the problem results that the entericcoating is partly dissolved or even dissolved from inside because of thealkaline medium in the interior and the free carboxyl groups promote thedecomposition of the active compounds. It is therefore necessary toprovide an isolating intermediate layer (subcoating) between the entericcoating and the alkaline tablet core or pellet, it is proposed in EP-A-0244 380 to coat cores which contain the active compound together withalkaline compounds or as an alkaline salt with at least one layer ofnonacidic, inert pharmaceutically acceptable substances, which aresoluble in water or rapidly decompose in water, before the enteric layeris applied. The intermediate layer or intermediate layers act aspH-buffering zones in which the hydrogen ions diffusing in from outsidecan react with the hydroxyl ions diffusing from the alkaline core. Inorder to increase the buffer capacity of the intermediate layer, it isproposed to incorporate buffer substances into the intermediatelayer(s). In practice, it is possible by this process to obtain somewhatstable preparations. However, relatively thick intermediate layers areneeded in order to avoid the unsightly discolorations occurring even inthe case of only slight decomposition. Moreover, a considerable effortis to be made in the preparation to avoid traces of moisture.

In EP-A-0 519 365, a formulation on the principle of the alkaline corecoated with a water-soluble intermediate layer and an enteric coating isproposed for the active compound pantoprazole, in which improvedstability is achieved by use of polyvinylpyrrolidone and/orhydroxypropylmethylcellulose as binders for the alkaline core.

EP-A-0 342 522 discloses a formulation for acid-sensitive benzimidazolesin which, between the alkaline core and the enteric coating, anintermediate layer is located which is composed of only slightlywater-soluble film-forming material, such as ethylcellulose andpolyvinyl acetate, and a slightly water-soluble finely granularinorganic or organic material suspended therein, such as, for example,magnesium oxide, silicon oxide or sucrose fatty acid esters.

EP-A-0 277 741 describes spherical granules having a core which iscoated with spray powder, which contains low-substitutedhydroxypropylcellulose and a benzimidazole compound having anti-ulceractivity. These granules can be coated with an enteric coating agent.

WO 96/01623, WO 96/01624 and WO 96/01625 describe an administration formfor acid-labile H⁺/K⁺ ATPase inhibitors, in which the active compoundpellets are compressed together with tablet excipients to give a tablet.The pellets consist of cores which contain the acid-labile.H⁺/K⁺ ATPaseinhibitor together with alkaline compounds or as an alkaline salt. Thecores of the pellets are coated with one or more layers, at least onelayer having enteric properties. In a mechanical respect, the entericcoating must in this case be constituted such that on compression togive tablets the acid resistance of the pellets is not adverselyaffected. It is mentioned that the production of the cores of thepellets can be carried out by spray drying.

WO 97/25030 describes the processing of the abovementioned pellets togive an effervescent tablet.

WO 98/52564 describes a pharmaceutical composition in pellet form, whichhas an inert core, a benzimidazole on or in the core, amoisture-resistant layer around the core and an enteric coating over themoisture-resistant layer. Hydrophobic materials such as, for example,cetyl alcohol are mentioned as constituents of the moisture-resistantlayer.

EP-A-0 514 008 describes pharmaceutical administration forms foracid-labile benzimidazoles based on a solid matrix of a polyglycerolfatty acid ester or a lipid and the active compound. At least in thevicinity of the matrix surface, a substance is dispersed which developsviscosity on contact with water. It is mentioned that such anadministration form can settle in the digestive tract, remains there fora relatively long time and the bioavailability of the active compound isincreased.

As the abovementioned prior art shows, the production of peroraladministration forms for acid-labile active compounds requirestechnically complicated processes.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide a noveladministration form for acid-labile active compounds, which can beprepared without great technical effort and exhibits goodcontrollability of the release of active compound. A further object ofthe invention is the provision of an administration form in which theacid-labile active compound does not have to be protected by an entericcoating.

It has now surprisingly been found that this object can be achieved byan administration form which contains multiple individual activecompound units, the acid-labile active compound being present in theindividual active compound units in a matrix made of a mixture of atleast one fatty alcohol and at least one solid paraffin, being presentin a matrix made of a mixture of at least one triglyceride and at leastone solid paraffin or being present in a matrix made of a mixture of atleast one fatty acid ester and at least one solid paraffin.

One subject of the invention is therefore an administration form foracid-labile active compounds, comprising pharmaceutical excipients andmultiple individual active compound units, wherein the acid-labileactive compound is present in the individual active compound units in amatrix made of a mixture comprising at least one fatty alcohol and atleast one solid paraffin.

A further subject of the invention is also an administration form foracid-labile active compounds, comprising pharmaceutical excipients andmultiple individual active compound units, wherein the acid-labileactive compound is present in the individual active compound units in amatrix made of a mixture comprising at least one triglyceride and atleast one solid paraffin.

The invention furthermore relates to an administration form foracid-labile active compounds, comprising pharmaceutical excipients andmultiple individual active compound units, wherein the acid-labileactive compound is present in the individual active compound units in amatrix made of a mixture comprising at least one fatty acid ester and atleast one solid paraffin.

Further subjects follow from the patent claims.

The multiple individual active compound units (also described aspreparations below) within the meaning of the invention are multipleindividual units, in which at least one active compound particle ispresent in a matrix made of a mixture comprising at least one fattyalcohol and at least one solid paraffin, in a matrix made of a mixturecomprising at least one triglyceride and at least one solid paraffin orin a matrix made of a mixture comprising at least one fatty acid esterand at least one solid paraffin. Preferably, the active compound unitsare microspheres.

The active compound units according to the invention are distinguishedin particular by good stability, release of the active compound whichcan be controlled by means of the particle size, good flow behavior,good compressibility and by a constant (determined by the uniformsurface) release of active compound.

The particle size of the individual units is advantageously less than orequal to 2 mm, preferably from 50-800 μm, particularly preferably 50-700μm and very particularly preferably 50-600 μm. They are preferablymicrospheres having a particle size of 50-500 μm, particularlypreferably of 50-400 μm. They are particularly preferably monomodalmicrospheres having a particle size of 50-400 μm, particularlypreferably of 50-200 μm.

Acid-labile active compounds within the meaning of the present inventionare, for example, acid-labile proton pump inhibitors.

Acid-labile proton pump inhibitors (H⁺/K⁺ ATPase inhibitors) within themeaning of the present invention which may be mentioned are inparticular substituted pyridin-2-yl-methylsulfinyl-1H-benzimidazoles,such as are disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287,EP-A-0 174 726, EP-A-0 184 322, EP-A-0 261 478 and EP-A-0 268 956.Mention may preferably be made here of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole) and2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulfinyl}-1H-benzimidazole(INN: rabeprazole).

Further acid-labile proton pump inhibitors, for example substitutedphenylmethylsulfinyl-1H-benzimidazoles,cycloheptapyridin-9-ylsulfinyl-1H-benzimidazoles orpyridin-2-ylmethylsulfinylthienoimidazoles, are disclosed in DE-A-35 31487, EP-A-0 434 999 and EP-A-0 234 485. Examples which may be mentionedare 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]benzimidazole (INN:leminoprazole) and2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylsulfinyl)-1H-benzimidazole(INN: nepaprazole).

The acid-labile proton pump inhibitors are chiral compounds. The termacid-labile proton pump inhibitor also includes the pure enantiomers ofthe acid-labile proton pump inhibitors and their mixtures in any mixingratio. Pure enantiomers which may be mentioned by way of example are5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(INN: esomeprazole) and (−)-pantoprazole.

The acid-labile proton pump inhibitors are present here as such orpreferably in the form of their salts with bases. Examples of salts withbases which may be mentioned are sodium, potassium, magnesium andcalcium salts. If desired, the salts of the acid-labile proton pumpinhibitors with bases can also be present in hydrate form. Such ahydrate of the salt of an acid-labile proton pump inhibitor with a baseis disclosed, for example, in WO 91/19710.

Particularly preferred acid-labile proton pump inhibitors which may bementioned are pantoprazole sodium sesquihydrate (=pantoprazolesodium×1.5 H₂O), (−)-pantoprazole sodium sesquihydrate, omeprazolemagnesium, omeprazole, esomeprazole magnesium and esomeprazole.

The fatty alcohol is preferably a linear, saturated or unsaturatedprimary alcohol having 10-30 carbon atoms. It is preferably a primaryalcohol having 10 to 18 carbon atoms in linear chains. Fatty alcoholswhich may be mentioned by way of example are cetyl alcohol, myristylalcohol, lauryl alcohol or stearyl alcohol, cetyl alcohol beingpreferred. If desired, mixtures of fatty alcohols can also be present.

The triglyceride is glycerol whose three hydroxyl groups are esterifiedby carboxylic acids. Preferably, the carboxylic acids are monobasiccarboxylic acids having 8 to 22 carbon atoms, preferably naturallyoccurring carboxylic acids. In this context, they can be different or,preferably, identical carboxylic acids. Examples which may be mentionedare tristearate, tripalmitate and particularly preferably trimyristate(these triglycerides are commercially available under the name Dynasan118, 116 or 114). If desired, mixtures of triglycerides can also bepresent.

The fatty acid ester is the ester of an alcohol with a fatty acid. Inthis case, the alcohol is preferably a linear, saturated or unsaturatedprimary alcohol having 10-30, preferably having 12 to 18, carbon atoms.The fatty acid is preferably a monobasic carboxylic acid having 8 to 22,in particular 12 to 18, carbon atoms, preferably a naturally occurringcarboxylic acid. According to the invention, preferred fatty acid estersare those having a melting point of greater than 30° C. A fatty acidester which may be mentioned by way of example is cetyl palmitate, whichis commercially available, for example, under the name Cutina® CP. Ifdesired, mixtures of fatty acid esters can also be present.

The solid paraffin is preferably paraffinum solidum (paraffin wax).Alternatively, for example, ozocerite can also be used. If desired,mixtures can also be used.

If desired, the mixtures in the individual active compound units canhave one or more further pharmaceutically suitable excipients. Examplesof further suitable excipients which may be mentioned are polymers,sterols and basic compounds.

Examples of polymers which may be mentioned are povidone (e.g. Kollidon®17, 30 and 90 from BASF), vinylpyrrolidone/vinyl acetate copolymer andpolyvinyl acetate. Mention may furthermore be made of cellulose ethers[such as, for example methylcellulose, ethylcellulose (Ethocel®) andhydroxypropylmethylcellulose], cellulose esters [such as celluloseacetate phthalate (CAP), cellulose acetateltrimellitate (CAT),hydroxypropylmethylcellulose phthalate (HP50 and HP55) orhydroxypropylmethylcellulose acetate succinate (HPMCAS)], methacrylicacid/methyl methacrylate copolymer or methacrylic acid/ethylmethacrylate copolymer (Eudragit® L). The polymer is preferably povidoneor ethylcellulose. If desired, mixtures of polymers can also be present.By addition of suitable polymers, it is possible, for example, toinfluence the properties of the individual active compound unitspharmaceutically (e.g. release of the active compound). By addition ofsuitable polymers such as cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate (HP50 and HP55), a gastric juiceresistance (delayed release according to definition of United StatesPharmacopeia) of the individual active compound units can be achieved.For the production of an active compound unit having controlled release(extended release according to definition of United States Pharmacopeia)of the active compound, it is possible to add suitable polymers such asethylcellulose and cellulose acetate.

The sterol is preferably a phytosterol or a zoosterol. Examples ofphytosterols which may be mentioned are ergosterol, stigmasterol,sitoisterol, brassicasterol and campesterol. Examples of zoosterolswhich may be mentioned are cholesterol and lanosterol. If desired,mixtures of sterols can also be present.

Suitable basic compounds are, for example, inorganic basic salts such asammonium carbonate and sodium carbonate, amines such as meglumine, di-or triethylamine and TRIS (2-amino-2-hydroxymethyl-1,3-propandiol) orfatty amines such as stearylamine. Stearylamine may be preferablymentioned. By the addition of basic compounds to the mixtures in theindividual units, particularly stable preparations are obtained andpossible discolorations are avoided.

The proportion (in percent by weight) of active compound in theindividual active compound unit is advantageously 1-90%. The proportionof active compound is preferably 2-70%, particularly preferably 5-40%,in particular 10-20%. The proportion of fatty alcohol in the individualactive compound unit is advantageously 10-70%, preferably 20-70%,particularly preferably 20-60% and in particular 30-60%. The proportionof triglyceride in the individual active compound unit is advantageously10-70%, preferably 20-70%, particularly preferably 20-60% and inparticular 30-60%. The proportion of fatty acid ester in the individualactive compound unit is advantageously 10-70%, preferably 20-70%,particularly preferably 20-60% and in particular 30-60%. The proportionof solid paraffin is advantageously 10-70%, preferably 20-60% and inparticular 30-60%. If present, the proportion of polymer in theindividual active compound unit is expediently 1-25%, preferably 1-10%,particularly preferably 5-10%. If present, the proportion of sterol isexpediently 1-10%, preferably 1-5%. If present, the proportion of basiccompound is 0.05-5%, preferably 0.1-1%.

Preferred individual active compound units according to the inventionconsist of 2-70% of active compound, 10-60% of fatty alcohol, 10-60% ofsolid paraffin, 1-15% of polymer and 0.1-2% of a basic compound. Furtherpreferred individual active compound units according to the inventionconsist of 2-70% of active compound, 10-60% of triglyceride, 10-60% ofsolid paraffin, 1-15% of polymer and 0.1-2% of a basic compound. Otherpreferred individual active compound units according to the inventionconsist of 2-70% of active compound, 10-60% of fatty acid ester, 10-60%of solid paraffin, 1-15% of polymer and 0.1-2% of a basic compound.

Particularly preferred individual active compound units according to theinvention consist of 5-40% of active compound, 20-60% of fatty alcohol,10-60% of solid paraffin, 1-15% of polymer and 0.1-1% of a basiccompound. Further particularly preferred individual active compoundunits according to the invention consist of 5-40% of active compound,20-60% of triglyceride, 10-60% of solid paraffin, 1-15% of polymer and0.1-1% of a basic compound. Other particularly preferred individualactive compound units according to the invention consists of 5-40% ofactive compound, 20-60% of fatty acid ester, 10-60% of solid paraffin,1-15% of polymer and 0.1-1% of a basic compound.

Examples of active compound units according to the invention contain5-40% of pantoprazole sodium sesquihydrate, 10-40% of cetyl alcohol,5-60% of solid paraffin, 1-5% of polymer and 0.1-0.2% of a basiccompound. Further examples of active compound units according to theinvention contain 5-40% of pantoprazole sodium sesquihydrate, 10-40% ofglyceryl tripalmitates, 5-60% of solid paraffin, 1-5% of polymer and0.1-0.2% of a basic compound. Still other examples of active compoundunits according to the invention contain 10-20% of pantoprazole sodiumsesquihydrate, 20-40% of triglyceride, 40-70% of solid paraffin, 1-5% ofsterol and 0.05-0.1% of a basic compound.

The individual active compound units can be prepared, for example, byspray drying or preferably by spray solidification, in particular alsoby spray prilling. The preparation is particularly preferably carriedout by prilling, in particular by vibration prilling. Spray drying iscarried out from a suitable solvent. Suitable solvents for spray dryingare preferably those in which the fatty alcohol, the triglyceride or thefatty acid ester and the solid paraffin are soluble, while the activecompound is insoluble. The suitable solvents can also be solventmixtures.

If the active compound employed is an acid-labile proton pump inhibitor,in particular a substituted pyridin-2-ylmethylsulfinyl-1H-benzimidazole,the suitable solvents are, for example, hydrocarbons, chlorinatedhydrocarbons and ethyl acetate. Hydrocarbons which can be mentioned arein particular linear or branched alkanes or alternatively cycloalkanes.Examples of linear alkanes are pentane, hexane and heptane. Examples ofbranched alkanes which may be mentioned are 2-methylpentane and3-methylpentane. Examples of cycloalkanes which may be mentioned arecyclohexane and cyclopentane. If desired, mixtures of the hydrocarbonssuch as, for example, petroleum ether can also be employed. Achlorinated hydrocarbon which may be mentioned is chloroform or,preferably, dichloromethane.

For spray drying, the fatty alcohol, the triglyceride or the fatty acidester and the solid paraffin, and, if desired, the furtherpharmaceutical constituents are dissolved in the suitable solvent andthe active compound is suspended therein. If desired, the activecompound can also be suspended and the fatty alcohol, the triglycerideor the fatty acid ester and the solid paraffin can then be dissolved.The particle size of the active compound employed should in this caseadvantageously be less than 40 μm. The suspension obtained is thensprayed in a spray dryer.

Spray drying is carried out in a manner known per se. A detailedpresentation of this technique is found in K. Masters, Spray DryingHandbook, 5th Ed. 1991, and J. Broadhead, S. K. Edmond Ronan, C. T.Rhodes, The Spray Drying of Pharmaceuticals, Drug Dev. Ind. Pharm. 18,1169 (1992). The principle of spray drying consists in splitting up asolution or suspension of the product to be dried into fine droplets anddrying it with a hot stream of gas. The solid component remaining afterevaporation of the solvent is removed from the stream of gas by means ofa cyclone and/or by a filter unit and collected.

Suitable drying gases are, in particular, air and preferably nitrogen.The gas inlet temperature depends on the solvent.

The invention further relates to a preparation comprising an acid-labileactive compound, at least one fatty alcohol or at least one triglycerideor at least one fatty acid ester and at least one solid paraffin,obtainable by spray drying a suspension of the acid-labile activecompound in a solution of the fatty alcohol, the triglyceride or thefatty acid ester and the solid paraffin in a suitable solvent.

The preparation of the individual active compound units is preferablycarried out by spray solidification or by prilling, the preparation veryparticularly preferably being carried out by vibration prilling.

For spray solidification or prilling, the fatty alcohol, thetriglyceride or the fatty acid ester is expediently liquefied to give aclear melt together with the solid paraffin and, if desired, furtherexcipients. The active compound is dissolved or dispersed in thissolution and the solution or dispersion obtained is sprayed orpreferably prilled in a suitable device. A dispersion of the activecompound in a melt of the excipients is preferably used.

Spray solidification is carried out in a manner known per se. A detailedpresentation of this technique is found in P. B. Deasy,Microencapsulation and Related Drug Process (1984).

The preparation of the individual active compound units is particularlypreferably carried out by solidification from the liquid phase byproduction of droplets by means of vibrating nozzles and bysolidification of the droplets formed after stabilization thereof bydrying or cooling in a suitable medium (preferably gaseous or liquid).The suitable medium can be, for example, cooled gas such as air ornitrogen. Such a process is disclosed, for example, in DE 27 25 924. Thephase flowing to the nozzle is particularly preferably kept at aconstant temperature here. Solidification is preferably carried out bymeans of sudden quenching in a suitable cooling medium. In the prilling,the liquid phase flowing to the nozzle, the vibrating nozzle and thedrops formed by prilling are preferably kept, until the stabilization oftheir spherical form, at a constant temperature which is 1° C. to 10° C.above the melting temperature of the liquid phase, and thesolidification of the drops after stabilization thereof is carried outsuddenly by quenching using a gaseous or liquid cooling medium, whoseoperating temperature is at least 30° C. below the melting temperatureof the liquid phase. Such a process and a device suitable for carryingout this process are described, for example, in EP 0 467 221 B1. Forprilling by means of vibrating nozzles, suitable units are marketed, forexample, by Brace GmbH, Alzenau, Germany. With the aid of prilling bymeans of vibrating nozzles, the individual active compound units can beobtained in the form of microspheres having a narrow monomodal particlespectrum in the particle size range from 50 μm to 2 mm. Owing to thenarrow monomodal particle spectrum and a uniform, spherical form of themicrospheres thus obtained, a uniformly smooth surface, a uniform,defined delivery of active compound and, with respect to the gastricpassage in the case of oral administration forms (determined by thesmall particles), behavior like that of a solution is to be expected.The individual active compound units according to the invention thusdiffer from active compound-containing pellets obtained by extrusion.

In a further aspect, the invention therefore relates to microspherescomprising an acid-labile active compound and pharmaceuticallyacceptable excipients. The microspheres are preferably monomodalmicrospheres having a particle size range of 50-800 μm, preferably50-500 μm, particularly preferably 50-400 μm, in particular of 50-200μm. The microspheres preferably contain an acid-labile proton pumpinhibitor.

The invention further relates also to microspheres comprising anacid-labile active compound and at least one fatty alcohol as apharmaceutically acceptable excipient. In addition to the fatty alcohol,the microsphere can contain one or more further pharmaceuticallysuitable excipients. Examples of further suitable excipients which maybe mentioned are polymers, sterols and basic compounds, the termspolymers, sterols and basic compounds having the above-mentionedmeanings. In this case, the proportion (in percent by weight) of activecompound in the individual active compound unit is advantageously 1-90%.The proportion of active compound is preferably 2-70%, particularlypreferably 5-40%, in particular 10-20%. The proportion of fatty alcoholin the individual active compound unit is preferably 10-90%, preferably30-85%, particularly preferably 60-80%. If present, the proportion ofpolymer in the individual active compound unit is expediently 1-25%,preferably 1-10%, particularly preferably 5-10%. If present, theproportion of sterol is expediently 1-10%, preferably 1-5%. If present,the proportion of basic compound is preferably 0.05-5%, preferably0.1-1%.

They are particularly preferably microspheres obtainable by productionof drops of a solution or dispersion of the acid-labile active compoundin at least one fatty alcohol by means of vibrating nozzles and bysolidification of the drops formed after stabilization thereof in asuitable medium. Preferably, the solution or dispersion flowing to thenozzle is kept at constant temperature.

The invention further relates to microspheres obtainable by productionof drops of a solution or dispersion of the acid-labile active compoundin at least one fatty alcohol, triglyceride or fatty acid ester togetherwith at least one solid paraffin by means of vibrating nozzles and bysolidification of the drops formed after stabilization thereof bycooling in a suitable medium. Preferably, the solution or dispersionflowing to the nozzle is kept at constant temperature.

The particle size of the active compound employed in the spray drying orspray solidification, prilling or vibration prilling is advantageouslyless than or equal to 100 μm, in particular less than 40 μm. Theparticle size is preferably in the range from 1-20 μm, particularlypreferably in the range from 3-15 μm. Such a particle size can beachieved, for example, by grinding the active compound in a suitablemill.

The individual active compound units (preparations) according to theinvention can then be used as a basis for the production of theadministration forms according to the invention. Administration formsaccording to the invention which may be mentioned, to which thepreparations can be processed, are, for example, suspensions, gels,tablets, coated tablets, multicomponent tablets, effervescent tablets,rapidly disintegrating tablets, powders in sachets, sugar-coatedtablets, capsules or alternatively suppositories. Preferredadministration forms here are peroral administration forms. Rapidlydisintegrating tablets and effervescent tablets are particularlypreferred. The excipients which are suitable for the desiredadministration forms are familiar to the person skilled in the art onthe basis of his/her expert knowledge. In the case of peroraladministration forms, it is surprisingly possible to dispense with theenteric coating.

The administration forms according to the invention contain theacid-labile active compound in the dose customary for the treatment ofthe respective disease. The acid-labile proton pump inhibitors accordingto the invention can be employed for the treatment and prevention of allthe diseases which are regarded as treatable or avoidable by the use ofpyridin-2-ylmethylsulfinyl-1H-benzimidazoles. In particular, suchadministration forms according to the invention can be employed in thetreatment of stomach disorders. Such administration forms according tothe invention contain between 1 and 500 mg, preferably between 5 and 60mg, of an acid-labile proton pump inhibitor. Examples which may bementioned are tablets or capsules which contain 10, 20, 40 or 50 mg ofpantoprazole. The administration of the daily dose (e.g. 40 mg of activecompound) can be carried out, for example, in the form of an individualdose or by means of a number of doses of the administration formsaccording to the invention (e.g. 2 times 20 mg of active compound).

The administration forms according to the invention can be combined withother medicaments, either in various combinations or in a fixedcombination. In connection with the administration forms according tothe invention which contain acid-labile proton pump inhibitors as activecompounds, combinations with antimicrobial active compounds andcombinations with NSAIDs (nonsteroidal antiinflammatory drugs) areworthy of mention. Combination with antimicrobial agents, such as areemployed for the control of the microorganism Helicobacter pylori (H.pylori), may particularly be mentioned.

Examples of suitable antimicrobial active compounds (active againstHelicobacter pylori) are described in EP-A-0 282 131. Examples ofantimicrobial agents suitable for the control of the microorganismHelicobacter pylori which may be mentioned are, for example, bismuthsalts [e.g. bismuth subcitrate, bismuth subsalicylate, ammoniumbismuth(III) potassium citrate dihydroxide, bismuth nitrate oxide,dibismuth tris(tetraoxodialuminate)], but in particular β-lactamantibiotics, for example penicillins (such as benzylpenicillin,phenoxymethylpenicillin, propicillin, azidocillin, dicloxacillin,flucloxacillin, oxacillin, amoxicillin, bacampicillin, ampicillin,meziocillin, piperacillin or aziocillin), cephalosporins (such ascefadroxil, cefaclor, cefalexin, cefixime, cefuroxime, cefetamet,cefadroxil, ceftibuten, cefpodoxime, cefotetan, cefazolin, cefoperazon,ceftizoxime, cefotaxime, ceftazidime, cefamandol, cefepime, cefoxitin,cefodizime, cefsulodin, ceftriaxon, cefotiam or cefmenoxime) or otherβ-lactam antibiotics (e.g. aztreonam, loracarbef or meropenem); enzymeinhibitors, for example sulbactam; tetracyclines, for exampletetracycline, oxytetracycline, minocycline or doxycycline;aminoglycosides, for example tobramycin, gentamicin, neomycin,streptomycin, amikacin, netilmicin, paromomycin or spectinomycin;amphenicols, for example chloramphenicol or thiamphenicol; lincomycinsand macrolide antibiotics, for example clindamycin, lincomycin,erythromycin, clarithromycin, spiramycin, roxithromycin or azithromycin:polypeptide antibiotics, for example colistin, polymixin B, teicoplaninor vancomycin; gyrase inhibitors, for example norfloxacin, cinoxacin,ciprofloxacin, pipemidic acid, enoxacin, nalidixic acid, pefloxacin.fleroxacin or ofloxacin; nitroimidazoles, for example metronidazole; orother antibiotics, for example fosfomycin or fusidic acid. Particularlyworthy of mention in this connection is the administration of anacid-labile proton pump inhibitor with the combination of a multiplicityof antimicrobial active compounds, for example with the combination of abismuth salt and/or tetracyclines with metronidazole or the combinationof amoxicillin or clarithromycin with metronidazole and amoxicillin withclarithromycin.

The production of administration forms and preparations according to theinvention is described by way of example below. The following examplesillustrate the invention in greater detail, without restricting it.

EXAMPLES Production of the Preparations Example 1

50 g of solid paraffin, 34.9 g of cetyl alcohol and 0.1 g ofstearylamine are fused to give a clear mixture. 5.0 g of povidone aredissolved in the clear melt. 10.0 g of pantoprazole sodium sesquihydrateare added and homogeneously suspended at a temperature of 56-60° C. Thesuspension is prilled in the molten state and the drops thus formed aresolidified in a cooling zone.

Example 2

55 g of solid paraffin, 30.9 g of cetyl alcohol and 0.1 g ofstearylamine are fused to give a clear mixture. 4.0 g of povidone aredissolved in the clear melt. 10.0 g of pantoprazole-magnesium are addedand homogeneously suspended at a temperature of 56-60° C. The suspensionis prilled in the molten state and the drops thus resulting aresolidified in a cooling zone.

Example 3

45.0 g of solid paraffin, 33.8 g of cetyl alcohol, 1.0 g of β-sitosteroland 0.2 g of stearylamine are fused to give a clear mixture. 1.0 g ofpovidone and 4.0 g of ethylcellulose are dissolved in the clear melt.15.0 g of pantoprazole sodium sesquihydrate are added and homogeneouslysuspended at a temperature of 56-60° C. The suspension is prilled in themolten state and the drops thus resulting are solidified in a coolingzone.

Example 4

52.0 g of solid paraffin, 30.3 g of cetyl alcohol and 0.2 g ofstearylamine are fused to give a clear mixture. 5.0 g of povidone aredissolved in the clear melt. 12.5 g of pantoprazole sodium sesquihydrateare added and homogeneously suspended at a temperature of 56-60° C. Thesuspension is prilled in the molten state and the drops thus formed aresolidified in a cooling zone.

Example 5

77.2 g of cetyl alcohol and 0.3 g of stearylamine are fused to give aclear mixture. 10.0 g of povidone are dissolved in the clear mixture.12.5 g of pantoprazole sodium sesquihydrate are added and homogeneouslysuspended at a temperature of 56-60° C. The suspension is prilled in themolten state and the drops thus formed are solidified in a cooling zone.

Example 6

47 g of solid paraffin, 40 g of glyceryl tripalmitate (Dynasan 116,Hüls), and 3 g of sitosterol are fused to give a clear mixture at 100°C. and cooled to 55-60° C. 10 g of lansoprazole are added andhomogeneously suspended. The suspension is added to the feed containerof a prilling unit (Brace) and prilled at about 0.1 bar from a 200 μmnozzle. A periodic oscillation of the frequency of about 390 Hz istransmitted to the nozzle head in the course of this. The resultingdrops are solidified in a cooling zone using air with a temperature of−30° C.

Example 7

15 g of glyceryl trimyristate (Dynasan 114), 15 grams of glyceryltripalmitate (Dynasan 116), 50 grams of solid paraffin and 5 g ofcholesterol are fused to give a clear mixture at about 100° C. The clearmelt is cooled to about 55-65° C. 15 g of rabeprazole are added, thecompound is distributed uniformly and the homogeneous suspension isprilled as in Example 6.

Example 8

10 g of glyceryl tripalmitate (Dynasan 116), 20 g of glyceryltrimyristate (Dynasan 114), 52 g of solid paraffin and 3 g of sitosterolare fused to give a clear mixture at about 100° C. The clear melt iscooled to 55-65° C. 15 g of omeprazole Mg are added and homogeneouslysuspended. The suspension is added to the feed container of a prillingunit (Brace) and prilled at 90 mbar by means of a 200 μm nozzle. Aperiodic oscillation of the frequency of about 400 Hz is transmitted tothe nozzle head in the course of this. The resulting drops aresolidified in a cooling zone using air with a temperature of −30° C.

Example 9

18 g of tristearate, 60 g of solid paraffin and 5 g of cholesterol arefused to give a clear mixture. The clear melt is cooled to 56-60° C. 10g of pantoprazole sodium sesquihydrate are introduced and this ishomogeneously dispersed. The suspension is prilled in the molten statein a prilling unit (Brace) having vibrating nozzles and the resultingdrops are solidified in a cooling zone.

Example 10

18 g of cetyl palmitate, 40 g of solid paraffin and 2 g of cholesterolare fused to give a clear mixture. The clear melt is cooled to 56-60° C.10 g of pantoprazole sodium sesquihydrate are introduced and homogenizeduntil a uniform suspension is formed. The liquid suspension is prilledin the molten state in a prilling unit (Brace) having vibrating nozzlesand the resulting drops are solidified in a cooling zone.

Example 11

50 g of solid paraffin and 40 g of cetyl palmilate (Cutina® CP) arefused to give a clear mixture at 100° C. The clear melt is cooled to50-60° C. 10 g of pantoprazole sodium sesquihydrate are introduced andhomogeneously suspended. The liquid suspension is prilled in the moltenstate in a prilling unit (Brace) having vibrating nozzles (200 μmnozzle) and the resulting drops are solidified in a cooling zone.

Example 12

50 g of solid paraffin and 40 g of cetyl alcohol are fused to give aclear mixture at 100° C. The clear melt is cooled to 50-60° C. 10 g ofpantoprazole sodium sesquihydrate are introduced and homogeneouslysuspended. The liquid suspension is prilled in the molten state in aprilling unit (Brace) having vibrating nozzles (200 μm nozzle) and theresulting drops are solidified in a cooling zone.

Example 13

50 g of solid paraffin and 40 g of glyceryl trimyristate are fused togive a clear mixture at 100° C. The clear melt is cooled to 50-60° C. 10g of pantoprazole sodium sesquihydrate are introduced and homogeneouslysuspended. The liquid suspension is prilled in the molten state in aprilling unit (Brace) having vibrating nozzles (200 μm nozzle) and theresulting drops are solidified in a cooling zone.

Example 14

47 g of solid paraffin, 40 g of glyceryl tripalmitate (Dynasan 116,Hüls) and 3 g of sitosterol are fused to give a clear mixture at 100° C.and cooled to 55-60° C. 10 g of lansoprazole are added and homogeneouslysuspended. The suspension is added to the feed container of a prillingunit (Brace) and prilled at about 0.1 bar from a 200 μm nozzle. Aperiodic oscillation of the frequency of about 390 Hz is transmitted tothe nozzle head in the course of this. The resulting drops aresolidified in a cooling zone using air with a temperature of −30° C.

Example 15

30 g of tristearate, 60 g of solid paraffin, 4 g of sitosterol and 0.07g of stearylamine are fused to give a clear mixture. The clear melt iscooled to 56-60° C. 15 g of pantoprazole sodium sesquihydrate areintroduced and this is homogeneously dispersed. The suspension isprilled in the molten state in a prilling unit (Brace) having vibratingnozzles and the resulting drops are solidified in a cooling zone.

The preparations obtained according to Examples 1-15 have a particlesize in the range 50-700 μm. By variation of the process conditions itis possible, for example, to obtain larger particles.

Preparation of the Administration Forms Example A

134.7 g of mannitol, 30 g of Kollidon® 30 and 20 g of xanthan are mixedin dry form. The mixture is granulated in a fluidized bed granulatorusing water. Granules having a particle size of 0.8-1.5 mm are obtained,which are mixed with the preparation (125 g) obtained according toExample 1. The mixture thus obtained is dispensed into sachets orcompressed to give tablets—if desired together with further tabletexcipients—in a manner known to the person skilled in the art.

Example B

An amount of the preparation obtained according to Example 2corresponding to 22.6 mg of pantoprazole magnesium is mixed with 500 mgof lactose and 100 mg of xanthan. Depending on individual sense oftaste, the mixture is additionally mixed with flavorings (sweetener,aroma) and then dispensed into a sachet. By dissolving the contents of asachet in a glass of water with stirring, a suspension for oraladministration is obtained.

Example C

An amount of the preparation from Example 3 corresponding to 45.2 mg ofpantoprazole sodium sesquihydrate is mixed with the corresponding amountof lactose. This mixture is mixed with a mixture of citric acid andsodium carbonate. After addition of a suitable lubricant (e.g. sodiumstearyl fumarate) and addition of one or more suitable flavorings, themixture obtained is compressed directly (without further granulation) togive an effervescent tablet. By dissolving a tablet in a glass of water,a suspension for oral administration is obtained.

Example D

An amount of the preparation according to Example 4 corresponding to45.2 mg of pantoprazole sodium sesquihydrate is mixed with lactose toimprove the flow properties. The mixture is dispensed into hard gelatincapsules of suitable size together with other suitable active compounds(e.g. amoxicillin or NSAIDs in customary dose forms).

Example E

300 mg of lactose are added to an amount of the preparation according toExample 6 comprising 30 mg of lansoprazole. The two components are mixedwith citric acid and sodium carbonate and, after addition of a suitablelubricant (e.g. sodium stearyl fumarate) and addition of suitableflavorings, compressed to give a tablet.

Example F

450 mg of sucrose and 300 mg of xanthan are added to an amount of thepreparation according to Example 7 corresponding to 30 mg ofrabeprazole. The components are mixed and treated with flavorcorrigents. The granules are filled into sachets. The contents of asachet can be added to a glass of water and, after stirring, are readyfor use.

Example G

60 grams of the preparation according to Example 8 are mixed in dry formwith 140 grams of mannitol, 30 grams of Kollidon 30 and 20 grams ofxanthan. The mixture is granulated with water in a fluidized bedgranulator. Granules are obtained with the particle size 0.8-1.5 mm. Themixture thus obtained is dispensed into sachets.

1. An oral solid active compound unit comprising a solidified drop, thesolidified drop comprising: a matrix comprising a mixture of cetylpalmitate or at least one triglyceride selected from the groupconsisting of tristearate, tripalmitate and trimyristate, and at leastone solid paraffin; and an acid-labile active compound selected from thegroup consisting of substitutedpyridin-2-yl-methylsulfinyl-1H-benzimidazoles, substitutedphenylmethylsulfinyl-1H-benzimidazoles, substitutedcycloheptapyridin-9-ylsulfinyl-1H-benzimidazoles and substitutedpyridin-2-ylmethylsulfinyl-thienoimidazoles, wherein said acid-labileactive compound is present in said matrix, and wherein the solidifieddrop does not comprise an enteric coating.
 2. The oral solid activecompound unit as claimed in claim 1, wherein the matrix furthercomprises one or more excipients selected from the group consisting ofpolymers, sterols and basic compounds.
 3. The oral solid active compoundunit as claimed in claim 1, wherein the acid-labile active compound isselected from the group consisting of omeprazole, pantoprazole,lansoprazole and rabeprazole.
 4. The oral solid active compound unit asclaimed in claim 1, wherein the acid-labile active compound ispantoprazole sodium sesquihydrate, (−)-pantoprazole sodiumsesquihydrate, omeprazole magnesium, omeprazole, esomeprazole magnesiumor esomeprazole.
 5. The oral solid active compound unit as claimed inclaim 1, wherein the acid-labile active compound is pure enantiomer. 6.The oral solid active compound unit as claimed in claim 1, wherein theacid-labile active compound is esomeprazole or (−)-pantoprazole.
 7. Theoral solid active compound unit as claimed in claim 1, wherein thesolidified drop has a particle size range of 50-800 μm.
 8. The oralsolid active compound unit as claimed in claim 1, wherein the solidifieddrop has a particle size range of 50-400 μm.
 9. The oral solid activecompound unit as claimed in claim 1, wherein the solidified drop has aparticle size range of 50-200 μm.
 10. The oral solid active compoundunit as claimed in claim 1, wherein the solid paraffin is paraffinumsolidum or ozocerite.
 11. The oral solid active compound unit as claimedin claim 1, wherein the acid-labile active compound is 1-90% by weightof the oral solid active compound unit.
 12. The oral solid activecompound unit as claimed in claim 11, wherein the acid-labile activecompound is 2-70% by weight of the oral solid active compound unit. 13.The oral solid active compound unit as claimed in claim 11, wherein theacid-labile active compound is 5-40% by weight of the oral solid activecompound unit.
 14. The oral solid active compound unit as claimed inclaim 11, wherein the acid-labile active compound is 10-20% by weight ofthe oral solid active compound unit.
 15. The oral solid active compoundunit as claimed in claim 1, wherein the solid paraffin is 10-70% byweight of the oral solid active compound unit.
 16. The oral solid activecompound unit as claimed in claim 15, wherein the solid paraffin is30-60% by weight of the oral solid active compound unit.
 17. The oralsolid active compound unit as claimed in claim 15, wherein the solidparaffin is 20-60% by weight of the oral solid active compound unit. 18.The oral solid active compound unit as claimed in claim 1, wherein theacid-labile active compound is selected from the group consisting of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl)-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole),2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulfinyl)-1H-benzimidazole(INN: rabeprazole),2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]benzimidazole (INN:leminoprazole),2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta-[b]-pyridin-9-ylsulfinyl)-1H-benzimidazole(INN: nepaprazole),5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(INN: esomeprazole), (−)-pantoprazole, pantoprazole sodiumsesquihydrate, (−)-pantoprazole sodium sesquihydrate, omeprazolemagnesium, omeprazole, esomeprazole magnesium and esomeprazole.